Although incredibly complex, we love hearing about the latest scientific reproductive breakthroughs that could potentially transform lives by helping people create their families. Here, we look at the emergence of a powerful new technology known as in vitro gametogenesis (IVG).
Infertility affects approximately 1 in 6 people worldwide during their lifetime, according to the World Health Organization (WHO). The American Society for Reproductive Medicine (ASRM) defines infertility as a condition characterized by the inability to achieve a successful pregnancy based on medical, sexual, and reproductive history, age, physical findings, diagnostic testing, or requiring medical intervention like the use of mature donor gametes to achieve pregnancy.
Although assisted reproductive technologies (ARTs), such as in vitro fertilization (IVF), have significantly impacted treating certain forms of infertility, not all forms can be addressed with existing strategies. Recently, a powerful technology known as human in vitro gametogenesis (IVG) has emerged.
This method uses pluripotent stem cells (PSCs), such as induced pluripotent stem cells (iPSCs) from patients, to generate human germ cells with the potential to develop into mature gametes in culture.
This offers a promising gateway to treating all forms of infertility, regardless of gender.
However, human IVG research is still in its infancy, with the current goal being to reconstitute the complete process of human gametogenesis. A major challenge has been to replicate a crucial event known as epigenetic reprogramming in human primordial germ cells (hPGCs), necessary for proper germ cell differentiation.
In a study published in Nature, researchers at the Institute for the Advanced Study of Human Biology (WPI-ASHBi) in Kyoto University, led by Dr. Mitinori Saitou, have identified robust culture conditions necessary to drive epigenetic reprogramming and germ cell differentiation into precursors of mature gametes. These include mitotic pro-spermatogonia and pro-oogonia capable of extensive amplification, marking a new milestone for human IVG research.
Previous work by Saitou’s team and others generated human primordial germ cell-like cells (hPGCLCs) from PSCs in vitro, which recapitulated several fundamental features of hPGCs, including the capacity to propagate. However, these hPGCLCs could not undergo epigenetic reprogramming and differentiation. While aggregating hPGCLCs with mouse embryonic gonadal cells could mimic the testis/ovary microenvironment and effectively “reconstitute” the tissue, this process was highly inefficient and impractical for clinical applications due to the introduction of non-human cells. Therefore, it was crucial to identify minimal culture conditions necessary to generate mature human gametes.
In their new study, Saitou and colleagues conducted a cell culture-based screen to identify potential signaling molecules required to drive epigenetic reprogramming and differentiation of hPGCLCs into mitotic pro-spermatogonia and oogonia. Surprisingly, they found that bone morphogenetic protein (BMP) played a crucial role in this process. The hPGCLC-derived mitotic pro-spermatogonia/oogonia displayed similarities in gene expression and epigenetic profiles to actual hPGC differentiation in the body and underwent extensive amplification (over 10 billion-fold). “Our approach enables near-indefinite amplification of mitotic pro-spermatogonia and oogonia in culture, and we now also have the ability to store and re-expand these cells as needed,” says Saitou.
The study also explored how BMP signaling might lead to epigenetic reprogramming and hPGCLC differentiation. BMP signaling appears to attenuate the MAPK/ERK signaling pathway and the activities of DNA methyltransferase (DNMT), but further investigation is necessary to determine the precise mechanism. “Our study represents not only a fundamental advance in our understanding of human biology and the principles behind epigenetic reprogramming in humans but also a true milestone in human IVG research,” says Saitou.
Although many challenges remain, particularly regarding the ethical, legal, and social implications associated with the clinical application of human IVG, this study marks a significant step forward towards the potential translation of IVG into reproductive medicine. These findings were published in Nature on May 20th, 2024.
To all the scientists in the world, we salute you for your hard work, skill and dedication.
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